Loss of skin elasticity is associated with pulmonary emphysema, biomarkers of inflammation, and matrix metalloproteinase activity in smokers

Abstract

Background: Elastin breakdown and the resultant loss of lung elastic recoil is a hallmark of pulmonary emphysema in susceptible individuals as a consequence of tobacco smoke exposure. Systemic alterations to the synthesis and degradation of elastin may be important to our understanding of disease phenotypes in chronic obstructive pulmonary disease. We investigated the association of skin elasticity with pulmonary emphysema, obstructive lung disease, and blood biomarkers of inflammation and tissue protease activity in tobacco-exposed individuals.

Methods: Two hundred and thirty-six Caucasian individuals were recruited into a sub-study of the University of Pittsburgh Specialized Center for Clinically Orientated Research in chronic obstructive pulmonary disease, a prospective cohort study of current and former smokers. The skin viscoelastic modulus (VE), a determinant of skin elasticity, was recorded from the volar forearm and facial wrinkling severity was determined using the Daniell scoring system.

Results: In a multiple regression analysis, reduced VE was significantly associated with cross-sectional measurement of airflow obstruction (FEV1/FVC) and emphysema quantified from computed tomography (CT) images, β = 0.26, p = 0.001 and β = 0.24, p = 0.001 respectively. In emphysema-susceptible individuals, elasticity-determined skin age was increased (median 4.6 years) compared to the chronological age of subjects without emphysema. Plasma biomarkers of inflammation (TNFR1, TNFR2, CRP, PTX3, and SAA) and matrix metalloproteinase activity (MMP1, TIMP1, TIMP2, and TIMP4) were inversely associated with skin elasticity.

Conclusions: We report that an objective non-invasive determinant of skin elasticity is independently associated with measures of lung function, pulmonary emphysema, and biomarkers of inflammation and tissue proteolysis in tobacco-exposed individuals. Loss of skin elasticity is a novel observation that may link the common pathological processes that drive tissue elastolysis in the extracellular matrix of the skin and lung in emphysema-susceptible individuals.

Keywords: COPD; Elasticity; Emphysema; Inflammation; Metalloprotease; Skin.

Fig. 1

Measurement of facial wrinkling. Daniell system for scoring the appearance of facial wrinkles in the crow’s-foot area: 1) Essentially unwrinkled. 2) Between 2 and 6 wrinkles ≤3 cm in length. 3) Several prominent wrinkles 3-4 cm in length. 4) Wrinkles ≥5 cm in length, may extend onto cheek area. 5) Prominent wrinkles extending from crow’s-foot area over cheeks and forehead. 6) Profound wrinkling over most of the face

Fig. 2

Loss of skin elasticity is associated with greater impairment in lung function and increased pulmonary emphysema. Skin elasticity was associated with pulmonary emphysema determined by %LAA and Hist15. Skin elasticity was not associated with impairment in FEV1, however a significant association was observed between quartiles of skin elasticity and the severity of airflow obstruction, diffusion impairment, lung hyperinflation (RV/TLC) and pulmonary emphysema. Legend: FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity in 1 s; DLCO, diffusion capacity for carbon monoxide; LAA% = low attenuation areas, lung voxels with Hounsfield Unit (HU) values less than −950; Perc15, HU value at the 15th percentile of the HU value histogram of lung voxels

Fig. 3

Biological skin aging is accelerated in individuals with pulmonary emphysema. a Elasticity-determined skin age was visualized using linear regression modelling of VE against age following stratification for the presence or absence of visually-assessed pulmonary emphysema. b Enlarged view of regression model that depicts the linear intercept of VE (value 3.5) with ‘Emphysema’ (green arrow) and ‘No Emphysema’ (purple arrow), the distance between arrows highlights the difference in years between the two groups (Δ). c Subjects with visually-assessed pulmonary emphysema had lower skin elasticity at a given chronological age compared to current or former smokers without emphysema, consistent with an increased biological age of skin in the emphysema group. Legend: VE; skin elasticity; Δ, delta/difference